Inflammation and traumatic skeletal muscle injury.
Summan-M; Hulderman-T; Matheson-JM; Simeonova-PP
Toxicologist 2004 Mar; 78(S-1):95-96
Traumatic skeletal muscle injuries result in profound histopathological changes and loss of muscle function. These injuries result in local infiltration of large numbers of mononuclear cells, degeneration of injured myofibers and phagocytic removal of cell debris. Macrophages are critical effector cells in host defense and release a diverse array of cellular mediators including cytotoxic and proinflammatory cytokines that contribute to tissue injury. The present study evaluated the role of systemic macrophages in the injury/repair mechanisms in a traumatic skeletal muscle injury model using liposome encapsulated clodronate, a drug with well characterized monocyte/macrophage depleting qualities. C57BL/6 mice (n = 4 per group) were injected with clodronate liposomes 48 and 2 hours prior to the freeze injury of the left tibialis anterior (TA) muscle and every third day during the post-injury period. Control mice received phosphate buffered saline (PBS) liposomes. At 1, 3, 9 or 14 days post-injury, TA muscles were harvested for histology, immunohistochemistry or gene expression evaluation by quantitative real time RT-PCR. Histopathology revealed less inflammatory cell infiltration in the injured muscle of clodronate treated mice at day 3 post-injury, delayed muscle tissue recovery and impaired clearance of necrotic myofibers at day 9 post-injury; and increased fat infiltration at day 14 post-injury. Immunohistochemical evaluation of injured muscle demonstrated that Mac-1 expression was dramatically reduced in clodronate treated mice at day 3 post-injury. Clodronate treatment also significantly attenuates inflammatory (TNF-alpha, Mac-1 and MCP-1), growth (IGF-BP) factor and antioxidant (thioredoxin) gene expression in injured TA muscle compared to injured non-treated TA muscle. In conclusion, the inhibition of the inflammatory response resulted in delayed phagocytosis of the necrotic myofibers and delayed the repair process of the injured muscle tissue. Selective and time dependent modulation of the innate immune system may provide optimal resolution of skeletal muscle injury.
Musculoskeletal-system-disorders; Muscles; Injuries; Traumatic-injuries; Muscle-function; Models; Laboratory-animals; Animals; Animal-studies; Muscular-disorders
Research Tools and Approaches: Exposure Assessment Methods
The Toxicologist. Society of Toxicology 43nd Annual Meeting and ToxExpo, March 21-25, 2004, Baltimore, Maryland